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BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months.METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812.FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups.INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale.FUNDING: Fonds NutsOhra.

Background Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this “off-hours effect” also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands. Methods Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009–2015, EVT: 2014–2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values. Results In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7–4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI − 4.2 to 18.1). Clinical outcome and sICH rate also did not differ. Conclusion Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

Background and ObjectivesThe ULTRA trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at 6 months. An expected proportion of the included patients experienced nonaneurysmal subarachnoid hemorrhage. In this post hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at 6 months.MethodsThe ULTRA trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013, and January 20, 2020. After confirmation of subarachnoid hemorrhage on noncontrast CT, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care or usual care only. In this post hoc analysis, we included all ULTRA participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin scale (mRS), dichotomized into good (0–3) and poor (4–6) outcomes.ResultsOf the 813 ULTRA trial patients who experienced an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio [aOR] 0.92; 95% CI 0.69–1.24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0–2) (aOR 0.76; 95% CI 0.57–1.03), all-cause mortality at 30 days (aOR 0.91; 95% CI 0.65–1.28), and all-cause mortality at 6 months (aOR 1.10; 95% CI 0.80–1.52).DiscussionUltra-early and short-term tranexamic acid treatment did not improve clinical outcomes at 6 months in patients with aneurysmal subarachnoid hemorrhage and therefore cannot be recommended.Trial Registration InformationClinicalTrials.gov(NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013).Classification of EvidenceThis study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Background: Patients with large vessel occlusion (LVO) stroke are often initially admitted to a primary stroke center (PSC) and subsequently transferred to a comprehensive stroke center (CSC) for endovascular thrombectomy (EVT). This interhospital transfer delays initiation of EVT. To identify potential workflow improvements, we analyzed pre- and interhospital time metrics for patients with LVO stroke who were transferred from a PSC for EVT.Methods: We used data from the regional emergency medical services and our EVT registry. We included patients with LVO stroke who were transferred from three nearby PSCs for EVT (2014–2021). The time interval between first alarm and arrival at the CSC (call-to-CSC time) and other time metrics were calculated. We analyzed associations between various clinical and workflow-related factors and call-to-CSC time, using multivariable linear regression.Results: We included 198 patients with LVO stroke. Mean age was 70 years (±14.9), median baseline NIHSS was 14 (IQR: 9–18), 136/198 (69%) were treated with intravenous thrombolysis, and 135/198 (68%) underwent EVT. Median call-to-CSC time was 162 min (IQR: 137–190). In 133/155 (86%) cases, the ambulance for transfer to the CSC was dispatched with the highest level of urgency. This was associated with shorter call-to-CSC time (adjusted β [95% CI]: −27.6 min [−51.2 to −3.9]). No clinical characteristics were associated with call-to-CSC time.Conclusion: In patients transferred from a PSC for EVT, median call-to-CSC time was over 2.5 h. The highest level of urgency for dispatch of ambulances for EVT transfers should be used, as this clearly decreases time to treatment.

Centralization of intravenous thrombolysis (IVT) for acute ischemic stroke in high-volume centers is believed to improve the door-to-needle times (DNT), but limited data support this assumption. We examined the association between DNT and IVT volume in a large Dutch province. We identified consecutive patients treated with IVT between January 2009 and 2013. Based on annualized IVT volume, hospitals were categorized as low-volume (≤ 24), medium-volume (25-49) or high-volume (≥ 50). In logistic regression analysis, low-volume hospitals were used as reference category. Of 17,332 stroke patients from 11 participating hospitals, 1962 received IVT (11.3 %). We excluded 140 patients because of unknown DNT (n = 86) or in-hospital stroke (n = 54). There were two low-volume (total 101 patients), five medium-volume (747 patients) and four high-volume hospitals (974 patients). Median DNT was shorter in high-volume hospitals (30 min) than in medium-volume (42 min, p < 0.001) and low-volume hospitals (38 min, p < 0.001). Patients admitted to high-volume hospitals had a higher chance of DNT < 30 min (adjusted OR 3.13, 95 % CI 1.70-5.75), lower risk of symptomatic intracerebral hemorrhage (adjusted OR 0.39, 95 % CI 0.16-0.92), and a lower mortality risk (adjusted OR 0.45, 95 % CI 0.21-1.01), compared to low-volume centers. There was no difference in DNT between low- and medium-volume hospitals. Onset-to-needle times (ONT) did not differ between the groups. Hospitals in this Dutch province generally achieved short DNTs. Despite this overall good performance, higher IVT volumes were associated with shorter DNTs and lower complication risks. The ONT was not associated with IVT volume

Background: Unruptured intracranial aneurysms can be preventively treated by surgical clipping or endovascular coiling. We determined in detail the costs of these treatments. Methods: We included patients who were treated for an unruptured aneurysm between 1997 and 2003. Patients coiled in this period were matched with clipped patients according to the year of treatment, age and gender. Considering clipping and coiling, we compared all pre-admission costs of diagnostic procedures, all costs of treatment, and costs during follow-up including standard angiographic control examinations at 6 and 18 months after coiling. Costs were calculated as the product of the used resources and the costs of these resources. Results: The mean price for clipping was EUR 8,865.42 and that for coiling EUR 10,370.29. The difference was mainly determined by the higher material costs of coiling (EUR 5,300) compared with clipping (EUR 690). Costs of clipping were mainly determined by the need for intensive care facilities (1.2 days after clipping and 0 days after coiling) and the length of hospital stay (10.5 days after clipping and 3.4 days after coiling). After bootstrapping the data, costs of coiling were on average EUR 1,553 (95% confidence interval: EUR 1,539–1,569) higher than those of clipping. Conclusions: For unruptured intracranial aneurysms, direct in-hospital costs of coiling are on average higher than those of clipping, mostly because of the more expensive coils.